How to develop new systemic treatments in ultra-rare cancers with high unmet needs? The case of alveolar soft-part sarcoma.

Developing new drugs or generating evidence for existing drugs in new indications for ultra-rare cancers is complex and carries a high-risk of failure. This gets even harder in ultra-rare tumours, which have an annual incidence of 1 per 1,000,000 population or less. Here, we illustrate the problem of adequate evidence generation in ultra-rare tumours, using Alveolar Soft-Part Sarcomas (ASPS) - an ultra-rare sarcoma newly diagnosed in approximately 60 persons a year in the European Union - as an exemplar case showing challenges in development despite being potentially relevant for classes of agents. We discuss some possible approaches for addressing such challenges, especially focussing on constructive collaboration between academic groups, patients and advocates, drug manufacturers, and regulators to optimise drug development in ultra-rare cancers. This article, written by various European stakeholders, proposes a way forward to ultimately get better options for patients with ultra-rare cancers.

Mimicking angiogenic microenvironment of alveolar soft-part sarcoma in a microfluidic coculture vasculature chip.

Alveolar soft-part sarcoma (ASPS) is a slow-growing soft tissue sarcoma with high mortality rates that affects adolescents and young adults. ASPS resists conventional chemotherapy; thus, decades of research have elucidated pathogenic mechanisms driving the disease, particularly its angiogenic capacities. Integrated blood vessels that are rich in pericytes (PCs) and metastatic potential are distinctive of ASPS. To mimic ASPS angiogenic microenvironment, a microfluidic coculture vasculature chip has been developed as a three-dimensional (3D) spheroid composed of mouse ASPS, a layer of PCs, and endothelial cells (ECs). This ASPS-on-a-chip provided functional and morphological similarity as the in vivo mouse model to elucidate the cellular crosstalk within the tumor vasculature before metastasis. We successfully reproduce ASPS spheroid and leaky vessels representing the unique tumor vasculature to assess effective drug delivery into the core of a solid tumor. Furthermore, this ASPS angiogenesis model enabled us to investigate the role of proteins in the intracellular trafficking of bioactive signals from ASPS to PCs and ECs during angiogenesis, including Rab27a and Sytl2. The results can help to develop drugs targeting the crosstalk between ASPS and the adjacent cells in the tumoral microenvironment.

Atezolizumab as the First Systemic Therapy Approved for Alveolar Soft Part Sarcoma.

OBJECTIVE: The objective was to review the pharmacology, efficacy, and safety of atezolizumab (Tecentriq) for the treatment of adult and pediatric patients aged 2 years and older with unresectable or metastatic alveolar soft part sarcoma (ASPS). DATA SOURCES: A literature search was conducted using PubMed and MEDLINE databases, published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and May 31, 2023. Keywords included atezolizumab, Tecentriq, MPDL3280, immunotherapy, PD-L1, PD-1, pediatrics, sarcoma, and ASPS. STUDY SELECTION AND DATA EXTRACTION: All English-language studies involving atezolizumab for ASPS were included and discussed. DATA SYNTHESIS: Atezolizumab is an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody designed to block the interaction between PD-L1 and the programmed cell death protein 1 (PD-1) receptor. Atezolizumab was granted approval by the FDA specifically for ASPS based on a phase II clinical trial in adult and pediatric patients (n = 49), which reported an overall response rate of 24% and a durable response rate at 6 and 12 months of 67% and 42%, respectively. Common grade 3/4 adverse reactions include musculoskeletal pain (8%), followed by hypertension (6%), weight gain (6%), headache (4%), and dizziness (4%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Advanced ASPS is a high-risk disease with limited treatment options. Atezolizumab appears to be a viable treatment option in ASPS demonstrating clinical efficacy and a manageable toxicity profile. CONCLUSIONS: With no other treatments that are FDA approved specifically for ASPS, and few demonstrating efficacy in the advanced setting, the approval of atezolizumab, including the first approval for pediatric patients, represents a landmark improvement to the therapeutic arsenal against this rare disease.

Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.

BACKGROUND: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. MATERIALS AND METHODS: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. RESULTS: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. CONCLUSIONS: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.

Severe immediate hypersensitivity to gadolinium contrast agent after targeted treatment in a patient with alveolar soft part sarcoma: A case report and review of literature.

RATIONALE: Gadolinium-based contrast agents (GBCAs), benefiting from good tolerance and safety, become the priority contrast agents in magnetic resonance imaging. Serious hypersensitivity reactions caused by GBCAs are rare, but occur occasionally. The "immune surveillance" theory proposes that lowered immune function exists in patients with malignance, which decrease the occurrence of atopy. Natural immunosurveillance that enhanced by effective treatment of malignance may increase the risk of hypersensitivity. PATIENT CONCERNS: A 29-year-old female patient suffering from intensive pain with left leg mass was admitted in our hospital. DIAGNOSES: The patient was diagnosed with alveolar soft part sarcoma by histopathology and revealed destruction of the left fibula and lung metastasis by computed tomography scan, and treated with anlotinib hydrochloride, a multi-targeted tyrosine kinase inhibitor. After 4 cycles of effective targeted therapy, the patient developed severe immediate hypersensitivity due to gadopentetate dimeglumine-enhanced magnetic resonance imaging. INTERVENTIONS AND OUTCOMES: The vital signs of the patient returned to normal after rescue. Since then, the patient has not used gadolinium contrast agent again, and currently the condition is stable and still alive. LESSONS: Severe immediate hypersensitivity might be occurred by gadolinium contrast agent in patients with malignance after effective treatment. We explored the potential mechanism of GBCA-inducing hypersensitivity in detail, by especially focusing on the changes of immune environment. Furthermore, we propose new ideas for the safe use of GBCAs in patients with malignancies.

Exploratory study of an anti-PD-L1/TGF-ß antibody, TQB2858, in patients with refractory or recurrent osteosarcoma and alveolar soft part sarcoma: a report from Chinese sarcoma study group (TQB2858-Ib-02).

BACKGROUND: Novel and effective immunotherapies are required for refractory or recurrent sarcomas. Transforming growth factor-beta (TGF-ß) is a diverse regulatory and fibrogenic protein expressed in multiple sarcoma tumors that promotes epithelial-mesenchymal transition and excessive deposition of extracellular matrix. This study evaluated the efficacy and safety of the anti-PD-L1/TGF-ß antibody TQB2858 in patients with refractory osteosarcoma and alveolar soft part sarcoma (ASPS). METHODS: This single-arm phase 1b exploratory study included patients with refractory osteosarcoma or ASPS who had previously undergone at least two lines of systemic therapy. Patients were administered 1200 mg of TQB2858 once every 3 weeks. The primary endpoint was objective response rate (ORR), with null and alternative hypotheses of ORR ≤5% and ≥20%, respectively. Exploratory biomarker analyses using immunohistochemistry (IHC) staining (for PD-L1 and TGF-ß) were performed on pre-treatment tumor samples. RESULTS: Eleven eligible patients were included in this study. TQB2858 did not demonstrate evidence of efficacy as 0/5 osteosarcomas had any objective response, while 2/6 ASPS showed a partial response. The median progression-free survivals were 1.51 (1.38, Not Evaluable) and 2.86 (1.38, Not Evaluable) months for the osteosarcoma and ASPS groups, respectively. None of the administered cycles met the criteria for unacceptable toxicity. Other Grade 3 toxicities included abnormal liver function and elevation of γ-glutamyl transferase. IHC analysis revealed that functional enrichment in the TGF-ß pathway or PD-L1 was not associated with treatment outcomes. CONCLUSIONS: The combination of PD-L1 and TQB2858 did not significantly improve the ORR in patients with recurrent osteosarcoma. However, it improved immunogenic responses in ASPS, even after progression upon anti-PD-1/PD-L1 therapy, with an acceptable safety profile. IHC profiling with pathway enrichment analysis may not have any predictive value for survival outcomes. TRIAL REGISTRATION: Prospectively registered in the Ethical Review Committee of Peking University People's Hospital. The trial registration number is 2021PHA105-001 and 2021PHA140-001 and the registration date was March 2, 2022. CLINICALTRIALS: gov Identifier CTR20213001 and CTR20220390.

Atezolizumab for Advanced Alveolar Soft Part Sarcoma.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial.

BACKGROUND: Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas. METHODS: AcSé Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSé Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620. FINDINGS: Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13·1 months (range 0·1-52·8; IQR 4·3-19·7). At week 12, objective response rate was 6·2% (95% CI 2·3-13·0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause). INTERPRETATION: Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer. FUNDING: The Ligue contre le cancer, INCa, MSD. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Treatment of a case of primary alveolar soft part sarcoma of the lung: Case report and literature review.

Alveolar soft part sarcoma (ASPS) is an extremely rare type of soft tissue sarcoma. The primary sites of ASPS are mostly located in the extremities and trunk. Primary pulmonary ASPS is extremely rare. A search of the PubMed® database identified only five cases of primary pulmonary ASPS. This current case report describes the sixth case of ASPS in a 15-year-old male that presented with recurrent headaches. Head computed tomography showed space-occupying lesions in the left parietal lobe. Positron emission tomography-computed tomography confirmed the space-occupying lesions in the left parietal lobe and showed multiple nodules and masses in the two lungs and pleura, which were considered to be low-grade malignant mesenchymal tumours. The case report presents the clinical characteristics, diagnosis and treatment process. Programmed cell death protein 1 monoclonal antibody (sintilimab) combined with a tyrosine kinase inhibitor (anlotinib hydrochloride) achieved a good therapeutic effect, indicating that this combination therapy is worth exploring further. Large-scale prospective studies are needed to explore and develop standardized treatments for ASPS.

Much Ado about ASPS: The Rapidly Changing Treatment Paradigms of 2022.

A recent randomized phase II study of sunitinib or cediranib in alveolar soft part sarcoma established benchmark activity for commonly used tyrosine kinase inhibitors (TKI). The impact of TKIs, as well as immunotherapy, has redefined treatment paradigms and greatly improved outcomes for this historically dismal sarcoma. See related article by Nguyen et al., p. 1200.

Examining Stripes on a Herd of Zebras: Impact of Genomic Matching for Ultrarare Sarcomas in Phase 1 Clinical Trials (SAMBA 102).

PURPOSE: Recently, the Connective Tissue Oncology Society published consensus guidelines for recognizing ultrarare sarcomas (URS), defined as sarcomas with an incidence ≤1 per 1,000,000. We assessed the outcomes of 56 patients with soft tissue, and 21 with bone sarcomas, enrolled in Phase 1 trials. EXPERIMENTAL DESIGN: In this Sarcoma-Matched Biomarker Analysis (SAMBA-102 study), we reviewed records from patients on Phase 1 trials at the University of Texas MD Anderson Cancer Center between January 2013 and June 2021. RESULTS: Among 587 sarcomas, 106 (18.1%) were classified as URS. Fifty (47%) were male, and the median age was 44.3 years (range, 19-82). The most common subtypes were alveolar soft part sarcoma (ASPS), chordoma, dedifferentiated chondrosarcoma, and sclerosing epithelioid fibrosarcoma. Compared with common sarcomas, median OS was similar 16.1 months [95% confidence interval (CI), 13.6-17.5] versus 16.1 (95% CI, 8.2-24.0) in URS (P = 0.359). Objective response to treatment was higher in URS 13.2% (n = 14/106) compared with common sarcomas 6.9% (n = 33/481; P = 0.029). Median OS for those treated on matched trials was 27.3 months (95% CI, 1.9-52.7) compared with 13.4 months (95% CI, 6.3-20.6) for those not treated on matched trials (P = 0.291). Eight of 33 (24%) molecularly matched treatments resulted in an objective response, whereas 6 of 73 unmatched treatments (8.2%) resulted in an objective response (P = 0.024). Clinical benefit rate was 36.4% (12/33) in matched trials versus 26.0% (19/73) in unmatched trials (P = 0.279). CONCLUSIONS: The results demonstrate the benefit of genomic selection in Phase 1 trials to help identify molecular subsets likely to benefit from targeted therapy.

Randomized Phase II Trial of Sunitinib or Cediranib in Alveolar Soft Part Sarcoma.

PURPOSE: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS. PATIENTS AND METHODS: Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined. RESULTS: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the two treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of four or six cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study. CONCLUSIONS: The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates. See related commentary by Wilky and Maleddu, p. 1163.

Treatment of metastatic alveolar soft part sarcoma with axitinib and pembrolizumab in an 80-year-old patient with a history of autoimmune disorders.

Alveolar soft part sarcoma (ASPS) is a rare malignancy with low sensitivity to chemotherapy. While localized ASPS has a very good prognosis after resection, the 5-year overall survival rate drops substantially in metastatic disease. We report the case of an 80-year-old male patient with ASPS of the left elbow and metastasis to the lung, lymph nodes and peritoneum. After weighing the benefits and risks, systemic treatment with the anti-PD-1 checkpoint inhibitor pembrolizumab combined with the vascular endothelial growth factor receptor tyrosinkinase inhibitor axitinib was initiated in this patient with a history of psoriasis and Crohn's disease. After only two cycles of therapy, a significant size reduction of the nodal cervical metastasis became apparent. A partial response of all metastases was then confirmed in the first computed tomography restaging. So far, side effects have remained manageable, especially with regard to the development or worsening of autoimmune adverse events. The patient continued to have a high quality of life, while also remaining in ongoing partial response for 15 months at the time of submission. While sarcomas generally have low sensitivity to immunotherapies, ASPS is an exception, and checkpoint inhibition is an integral part of its systemic therapy.

Comparative Combinatorial Implications and Theranostics of Immunotherapy in the Impediment of Alveolar Soft Part Sarcoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs), specifically programmed cell death receptor- 1/ligand 1 (PD-1/L1) inhibitors, have shown potential pharmacological efficacy in several cancers. Nonetheless, data pertinent to their therapeutic efficacy in alveolar soft-part sarcoma (ASPS) are limited. OBJECTIVE: The retrospective aspects of ICIs (anti-PD1/PD-L1 blockers) to target ASPS are comparatively analyzed for clinical outcomes with other targeted immunotherapy modalities. METHODS: We have conducted a systematic review without statistical analysis or comprehensive meta-analysis by collecting the articles published between 1952 and Sep 10th, 2020, by searching the following words: alveolar soft part sarcoma and immunotherapy including immune checkpoint, immune checkpoint inhibitors, and PD-1, PD-L1. We performed a pooled analysis of case reports, conferences, clinical trials, and other research reports pertinent to the efficacy of a PD-1 or PD-L1 antagonist in patients diagnosed with metastatic ASPS. RESULTS: The effective studies include 10 case reports, 2 conference reports, 5 clinical trials, and 2 additional research reports. A total of 110 patients were reported to be enrolled in the pooled analysis; among them, 87 (78.38%) received a PD-1/PD-L1 antagonist. For patients who received anti-PD-1/PD-L1as monotherapy, their clinical response rates (CRR) were 63.22% whereas those who received targeted therapy and immunotherapy had a CRR of 78.95% (15/19). In the patients treated with double immunotherapy, their CRR was 100% (4/4). Tumor mutational burden and mismatch repair status have significant implications for predicting the ASPS prognosis. CONCLUSION: Alveolar soft-part sarcoma patients with distant metastases can exhibit better clinical outcomes with immunotherapy, particularly toripalimab, atezolizumab, and axitinib combinatorial regimen with pembrolizumab. In addition, this review describes the therapeutic implications to guide personalized medicine depending on the expression patterns of PD-1/PD-L1 during the immunotherapy with ASPS.

Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial.

BACKGROUND: Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. METHODS: In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. FINDINGS: Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. INTERPRETATION: The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. FUNDING: AstraZeneca.

Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 "CREATE" Trial.

Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 "CREATE" phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan-Meier estimates, Cox regression, and the Fisher's exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy.

Combined immunotherapy and targeted treatment for primary alveolar soft part sarcoma of the lung: case report and literature review.

Primary acinar soft part sarcoma of the lung (ASPS) is a rare malignancy with unique cellular structure and clinical and genetic characteristics. Most patients do not exhibit clear clinical symptoms, with only a few developing respiratory symptoms. The typical histological characteristics are acinoid or organ-like structures. Immunofluorescence in situ hybridization suggests a rearrangement of the transcription factor E3 gene. Patients respond poorly to chemotherapy and are, thus, primarily treated with surgery and targeted therapy. We report herein a unique case of primary alveolar soft part sarcoma of the lung. The patient was a 24-year-old man with metastases to multiple organs, such as the brain, lungs, pancreas, and liver. The craniocerebral lesions attained partial remission after whole-brain radiotherapy and targeted combined immunotherapy, and other distant metastases completely disappeared after targeted combined immunotherapy (anlotinib and camrelizumab), indicating significant treatment efficacy. Anlotinib is an oral multi-target tyrosine kinase inhibitor (TKI) that exerts its anti-tumor effects by acting on various kinases. Camrelizumab is a humanized immunoglobulin G4 monoclonal antibody that can target PD-1 to block the interaction between PD-L1 and programmed death ligand 2, ultimately causing an anti-tumor effect. This is the first report of successful use of anlotinib combined with camrelizumab in the treatment of advanced primary ASPS. The treatment benefit provides preliminary evidence that targeted therapy, combined with immunotherapy, may be a safe and effective approach to treat primary pulmonary ASPS patients, thus warranting further investigation.

Successful treatment of advanced alveolar soft part sarcoma with camrelizumab combined with apatinib: a case report.

Alveolar soft part sarcoma (ASPS) is a rare and highly malignant mesenchymal tumor that primarily affects adolescents and young adults. ASPS is characterized by a slow growth rate, high metastatic potential, and resistance to conventional therapies. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced malignancies, improving the objective response rate (ORR) and prolonging patient survival. The combination of immunotherapy with targeted therapies can overcome resistance to treatment with ICIs alone. Although substantial progress has been made in various solid tumors, the clinical relevance of ICIs, used alone or in combination with other therapies, in patients with ASPS remains unclear. This is a case report of a 32-year-old man who was diagnosed with advanced ASPS. After 8 months of anlotinib treatment, the patient's disease progressed and new cerebellar metastases were detected. Radiotherapy was administered in addition to camrelizumab combined with apatinib to treat the brain metastases. The patient achieved partial remission (46%) after 3 months of treatment and did not present any severe side effects. This is the first reported case of the successful treatment of advanced ASPS with camrelizumab combined with apatinib. This case supports the use of a novel treatment regimen for patients with inoperable ASPS or ASPS that is resistant to conventional therapies.